IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis

1996 ◽  
Vol 270 (3) ◽  
pp. E430-E437 ◽  
Author(s):  
C. H. Lang ◽  
J. Fan ◽  
R. Cooney ◽  
T. C. Vary
Keyword(s):  
Protein Synthesis ◽  
Receptor Antagonist ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Abdominal Sepsis ◽  
Constant Infusion ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Igf I

The purpose of the present investigation was to determine whether endogenously produced interleukin (IL)-1 mediates the changes in insulin-like growth factor (IGF) I and IGF binding proteins (IGFBP) induced by chronic abdominal sepsis in rats and to correlate the changes in the IGF system with the alternations in protein synthesis. A constant infusion of IL-1 receptor antagonist (IL-1ra) was begun after the induction of sepsis and was continued for 5 days. Sepsis decreased IGF-I levels in the blood, liver, and gastrocnemius muscle, increased the content in the kidney, and did not alter IGF-I levels in heart, jejunum, and spleen. IL-1ra attenuated the sepsis-induced decrease in plasma IGF-I and completely prevented the changes in IGF-I observed in liver, kidney, and the gastrocnemius. IGFBP-1 was increased in the blood, liver, and muscle of septic rats. IL-1ra prevented this increase in IGFBP-1 in blood and liver but not in muscle. The rate of in vivo protein synthesis was decreased in the gastrocnemius and kidney and unaltered in the heart, liver, jejunum, and spleen. A strong linear correlation existed between levels of IGF-I and the rate of protein synthesis determined simultaneously in the gastrocnemius. These results provide evidence for the role of IL-1 as an endogenous mediator of the sepsis-induced changes in IGF-I and IGFBP-1 and suggest that the accompanying changes in muscle protein synthesis are partially mediated via changes in IGF-I.

The Time Course for Elevated Muscle Protein Synthesis Following Heavy Resistance Exercise

1995 ◽  
Vol 20 (4) ◽  
pp. 480-486 ◽  
Author(s):  
J. Duncan MacDougall ◽  
Martin J. Gibala ◽  
Mark A. Tarnopolsky ◽  
Jay R. MacDonald ◽  
Stephen A. Interisano ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Resistance Training ◽  
Time Course ◽  
Biceps Brachii ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Training Session ◽  
Constant Infusion ◽  
Heavy Resistance Training

It has been shown that muscle protein synthetic rate (MPS) is elevated in humans by 50% at 4 hrs following a bout of heavy resistance training, and by 109% at 24 hrs following training. This study further examined the time course for elevated muscle protein synthesis by examining its rate at 36 hrs following a training session. Six healthy young men performed 12 sets of 6- to 12-RM elbow flexion exercises with one arm while the opposite arm served as a control. MPS was calculated from the in vivo rate of incorporation of L-[1,2−13C2] leucine into biceps brachii of both arms using the primed constant infusion technique over 11 hrs. At an average time of 36 hrs postexercise, MPS in the exercised arm had returned to within 14% of the control arm value, the difference being nonsignificant. It is concluded that following a bout of heavy resistance training, MPS increases rapidly, is more than double at 24 hrs, and thereafter declines rapidly so that at 36 hrs it has almost returned to baseline. Key words: L-[−13C] leucine, muscle hypertrophy, training frequency, mass spectrometry

The use of doubly labeled milk protein to measure postprandial muscle protein synthesis rates in vivo in humans

2014 ◽  
Vol 117 (11) ◽  
pp. 1363-1370 ◽  
Author(s):  
Nicholas A. Burd ◽  
Naomi M. Cermak ◽  
Imre W. K. Kouw ◽  
Stefan H. Gorissen ◽  
Annemie P. Gijsen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Continuous Infusion ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Constant Infusion ◽  
Synthesis Rate ◽  
Mole Percent ◽  
Precursor Pool ◽  
The Impact

We aimed to determine the impact of precursor pool dilution on the assessment of postprandial myofibrillar protein synthesis rates (MPS). A Holstein dairy cow was infused with large amounts of L-[1-13C]phenylalanine and L-[1-13C]leucine, and the milk was collected and fractionated. The enrichment levels in the casein were 38.7 and 9.3 mole percent excess, respectively. In a subsequent human experiment, 11 older men (age: 71 ± 1 y, body mass index: 26 ± 0.1 kg·m−2) received a primed constant infusion of L-[ring-2H5]phenylalanine and L-[1-13C]leucine. Blood and muscle samples were collected before and after the ingestion of 20-g doubly labeled casein to assess postprandial MPS based on the 1) constant tracer infusion of L-[ ring-2H5]phenylalanine, 2) ingestion of intrinsically L-[1-13C]phenylalanine-labeled casein, and 3) constant infusion of L-[1-13C]leucine in combination with the ingestion of intrinsically L-[1-13C]leucine-labeled casein. Postprandial MPS was increased ( P < 0.05) after protein ingestion (∼70% above postabsorptive values) based on the L-[1-13C]leucine tracer. There was no significant stimulation of postprandial MPS (∼27% above postabsorptive values) when the calculated fractional synthesis rate was based on the L-[ring-2H5]phenylalanine ( P = 0.2). Comparisons of postprandial MPS based on the primed continuous infusion of L-[1-13C]leucine or the ingestion of intrinsically L-[1-13C]phenylalanine-labeled casein protein demonstrated differences compared with the primed continuous infusion of L-[ ring-2H5]phenylalanine ( P > 0.05). Our findings confirm that the postprandial MPS assessed using the primed continuous tracer infusion approach may differ if tracer steady-state conditions in the precursor pools are perturbed. The use of intrinsically doubly labeled protein provides a method to study the metabolic fate of the ingested protein and the subsequent postprandial MPS response.

IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids

1996 ◽  
Vol 270 (1) ◽  
pp. E60-E66 ◽  
Author(s):  
R. Jacob ◽  
X. Hu ◽  
D. Niederstock ◽  
S. Hasan ◽  
P. H. McNulty ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Plasma Insulin ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Amino Acid Replacement ◽  
Igf I ◽  
Awake Rat

Infusion of insulin-like growth factor I (IGF-I) lowers plasma amino acid and insulin concentrations, which may limit the capacity of IGF-I to promote muscle protein synthesis in vivo. We measured heart and skeletal muscle incorporation of continuously infused L-[ring-2,6-3H]phenylalanine in awake postabsorptive rats receiving 4-h intravenous infusions of saline (n = 11), IGF-I (1 microgram.kg-1.min-1) with (n = 10) or without (n = 11) amino acid replacement, or IGF-I with insulin replacement (n = 8). There were no significant increases in muscle protein synthesis during the infusion of IGF-I alone, which was associated with decreases in both plasma insulin (52 +/- 5%, P < 0.001) and amino acids (25 +/- 5%, P < 0.05). When IGF-I was given together with amino acids, protein synthesis was significantly increased in gastrocnemius (4.7 +/- 0.4 vs. 2.5 +/- 0.3%/day, P < 0.001), oblique (4.5 +/- 0.4 vs. 2.8 +/- 0.4%/day, P < 0.05), and soleus (8.8 +/- 0.7 vs. 6.4 +/- 0.3%/day, P < 0.01) and tended to be higher than saline control values in heart (10.9 +/- 0.9 vs. 8.8 +/- 0.7%/day, P = 0.08). Amino acid replacement prevented plasma concentrations from falling and also blunted the decline in plasma insulin (22 +/- 5%, P < 0.01 vs. IGF-I alone). When IGF-I and insulin replacement were given, protein synthesis was increased in heart (13.0 +/- 0.6%/day), gastrocnemius (4.7 +/- 0.4%/day), and oblique (4.5 +/- 0.4%/day) (P < 0.001 for each, compared with saline). We conclude that the action of IGF-I to acutely stimulate muscle protein synthesis in the awake rat is limited by the fall in circulating insulin and/or amino acid concentrations that accompanies IGF-I infusion in vivo and is prevented by co-infusion of insulin or amino acids.

Endotoxin-induced decrease in muscle protein synthesis is associated with changes in eIF2B, eIF4E, and IGF-I

2000 ◽  
Vol 278 (6) ◽  
pp. E1133-E1143 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost ◽  
Leonard S. Jefferson ◽  
Scot R. Kimball ◽  
Thomas C. Vary
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Translational Efficiency ◽  
Time Points ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Igf I ◽  
Vascular Catheters

The present study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle after administration of endotoxin (LPS). Rats implanted with vascular catheters were injected intravenously with a nonlethal dose of Escherichia coli LPS, and samples were collected at 4 and 24 h thereafter; pair-fed control animals were also included. The rate of muscle (gastrocnemius) protein synthesis in vivo was reduced at both time points after LPS administration. LPS did not alter tissue RNA content, but the translational efficiency was consistently reduced at both time points. To identify mechanisms responsible for regulating translation, we examined several eukaryotic initiation factors (eIFs). The content of eIF2α or the amount of eIF2α in the phosphorylated form did not change in response to LPS. eIF2B activity was decreased in muscle 4 h post-LPS but activity returned to control values by 24 h. A decrease in the relative amount of eIF2Bα protein was not responsible for the LPS-induced reduction in eIF2B activity. LPS also markedly altered the distribution of eIF4E in muscle. Compared with control values, LPS-treated rats demonstrated 1) a transient increase in binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF4E, 2) a transient decrease in the phosphorylated γ-form of 4E-BP1, and 3) a sustained decrease in the amount of eIF4G associated with eIF4E. LPS also decreased insulin-like growth factor (IGF) I protein and mRNA expression in muscle at both times. A significant linear relationship existed between muscle IGF-I and the rate of protein synthesis or the amount of eIF4E bound to eIF4G. In summary, these data suggest that LPS impairs muscle protein synthesis, at least in part, by decreasing translational efficiency, resulting from an impairment in translation initiation associated with alterations in both eIF2B activity and eIF4E availability.

scholarly journals Acute in Vivo Elevation of Insulin-Like Growth Factor (IGF) Binding Protein-1 Decreases Plasma Free IGF-I and Muscle Protein Synthesis

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3922-3933 ◽  
Author(s):  
Charles H. Lang ◽  
Thomas C. Vary ◽  
Robert A. Frost
Keyword(s):  
Protein Synthesis ◽  
Plasma Concentration ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Binding Protein ◽  
Igf I ◽  
Igf Binding ◽  
Fast Twitch ◽  
Igf Binding Protein

Abstract This study examined whether the acute elevation of IGF-binding protein-1 (IGFBP-1) decreases the plasma free IGF-I concentration and alters in vivo rates of muscle protein synthesis and glucose uptake. The plasma concentration of human IGFBP-1 was increased to approximately 95 ng/ml in conscious catheterized rats infused iv with human IGFBP-1 for 4 h. Infusion of IGFBP-1 also increased the concentration of endogenous (e.g. rat) IGFBP-1 in the blood, and this response was associated with a 2- to 3-fold elevation of IGFBP-1 mRNA in liver and kidney. IGFBP-1 did not significantly alter the plasma concentration of total IGF-I, but decreased circulating free IGF-I levels by about 50%. IGFBP-1 decreased protein synthesis in the predominantly fast-twitch gastrocnemius muscle (20%), and this change resulted from a decreased translational efficiency that was associated with a decreased phosphorylation of S6K1, but not 4E-BP1. Complementary studies demonstrated that IGFBP-1 also decreased the rates of protein synthesis under basal conditions and in response to stimulation by IGF-I when added in vitro to the fast-twitch epitrochlearis muscle. In contrast, IGFBP-1 did not alter in vivo-determined rates of protein synthesis in the slow-twitch soleus muscle, heart, liver, or kidney. The infusion of IGFBP-1 did not significantly alter the plasma glucose or lactate concentration or the whole body rate of glucose production or disposal. The above-mentioned changes were not mediated indirectly by changes in the plasma insulin or corticosterone concentrations, decreased high energy phosphate content in muscle, or hepatoxicity produced by the infused IGFBP-1. These results demonstrate that acute in vivo elevation in IGFBP-1, of the magnitude observed in various catabolic conditions, is capable of selectively decreasing protein synthesis in fast-twitch skeletal muscle and up-regulating the hepatic and renal syntheses of IGFBP-1 per se. Hence, elevations in circulating and tissue levels of IGFBP-1 may be an important mediator for the muscle catabolism observed in various stress conditions.

Chronic effects of β2 agonists on body composition and protein synthesis in the rat

1984 ◽  
Vol 4 (1) ◽  
pp. 83-91 ◽  
Author(s):  
P. W. Emery ◽  
N. J. Rothwell ◽  
M. J. Stock ◽  
P. D. Winter
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Binding Capacity ◽  
Body Weight Gain ◽  
Muscle Protein Synthesis ◽  
Body Protein ◽  
Fractional Rate ◽  
Brown Adipose ◽  
Β2 Agonists

Chronic treatment of rats with the β2-adrenergic agonists clenbuterol and fenoterol over 16–19 d raised energy intake, expenditure, and body weight gain but did not affect fat or energy deposition, and body protein gain was increased by 50 and 18%, respectively. Both drugs increased the protein content and mitochondrial GDP-binding capacity of brown adipose tissue. Clenbuterol did not affect plasma insulin, growth hormone, or triiodothyronine levels, although insulin levels were reduced by fenoterol. Both drugs caused hypertrophy of skeletal muscle (gastrocnemius), and muscle protein synthesis in vivo (fractional rate) was elevated by 34 and 26% in clenbuterol and fenoteroltreated rats, respectively.

Role of insulin and IGF-I in activation of muscle protein synthesis after oral feeding

1996 ◽  
Vol 270 (4) ◽  
pp. E614-E620 ◽  
Author(s):  
E. Svanberg ◽  
H. Zachrisson ◽  
C. Ohlsson ◽  
B. M. Iresjo ◽  
K. G. Lundholm
Keyword(s):  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Oral Feeding ◽  
Myofibrillar Proteins ◽  
Diabetic Mice ◽  
Igf I ◽  
Stimulation Of

The aim was to evaluate the role of insulin and insulin-like growth factor I (IGF-I) in activation of muscle protein synthesis after oral feeding. Synthesis rate of globular and myofibrillar proteins in muscle tissue was quantified by a flooding dose of radioactive phenylalanine. Muscle tissue expression of IGF-I mRNA was measured. Normal (C57 Bl) and diabetic mice (type I and type II) were subjected to an overnight fast (18 h) with subsequent refeeding procedures for 3 h with either oral chow intake or provision of insulin, IGF-I, glucose, and amino acids. Anti-insulin and anti-IGF-I were provided intraperitoneally before oral refeeding in some experiments. An overnight fast reduced synthesis of both globular (38 +/- 3%) and myofibrillar proteins (54 +/- 3%) in skeletal muscles, which was reversed by oral refeeding. Muscle protein synthesis, after starvation/ refeeding, was proportional and similar to changes in skeletal muscle IGF-I mRNA expression. Diabetic mice responded quantitatively similarly to starvation/refeeding in muscle protein synthesis compared with normal mice (C57 Bl). Both anti-insulin and anti-IGF-I attenuated significantly the stimulation of muscle protein synthesis in response to oral feeding, whereas exogenous provision of either insulin or IGF-I to overnight-starved and freely fed mice did not clearly stimulate protein synthesis in skeletal muscles. Our results support the suggestion that insulin and IGF-I either induce or facilitate the protein synthesis machinery in skeletal muscles rather than exerting a true stimulation of the biosynthetic process during feeding.

Enhanced response of muscle protein synthesis and plasma insulin to food intake in suckled rats

1993 ◽  
Vol 265 (2) ◽  
pp. R334-R340 ◽  
Author(s):  
T. A. Davis ◽  
M. L. Fiorotto ◽  
H. V. Nguyen ◽  
P. J. Reeds
Keyword(s):  
Protein Synthesis ◽  
Food Intake ◽  
Plasma Insulin ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fed State ◽  
Fasting And Refeeding ◽  
Old Rats ◽  
Amino Acid Concentrations

To compare the sensitivity of muscle protein synthesis to food intake in neonatal and weaned rats, 5- and 16-day-old suckled rats and 28-day-old weaned rats were either fed, fasted for 8-10 h, or refed for 1-4 h after an 8-h fast. Protein synthesis was measured in vivo in soleus and plantaris muscles with a large dose of L-[4-3H]phenylalanine. In fed rats, fractional rates of protein synthesis (KS) decreased with age. Fasting decreased KS, and refeeding increased KS most in 5-day-old animals, less in 16-day-old rats, and least in 28-day-old rats. In 5-day-old rats, there were no differences in KS between soleus and plantaris muscles in the fed state and after fasting and refeeding; at 28 days, KS was higher in soleus than in plantaris in fed rats, and the soleus did not respond to fasting and refeeding. In rats at all three ages, the concentration of most plasma amino acids decreased during fasting; when 5-day-old rats were refed, plasma amino acid concentrations increased, but not to the levels in the fed state. Plasma insulin concentrations increased with age. Plasma insulin concentrations decreased more rapidly with fasting and increased more extensively with refeeding in 5-day-old rats than in older rats. These results suggest that muscle protein synthesis is more responsive to food intake in young suckled rats than in older suckled or weaned rats; this increased responsiveness is accompanied by greater changes in circulating insulin concentrations.

Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans

1991 ◽  
Vol 260 (3) ◽  
pp. E499-E504 ◽  
Author(s):  
D. A. Fryburg ◽  
R. A. Gelfand ◽  
E. J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Igf I ◽  
Normal Humans

The short-term effects of growth hormone (GH) on skeletal muscle protein synthesis and degradation in normal humans are unknown. We studied seven postabsorptive healthy men (age 18-23 yr) who received GH (0.014 micrograms.kg-1.min-1) via intrabrachial artery infusion for 6 h. The effects of GH on forearm amino acid and glucose balances and on forearm amino acid kinetics [( 3H]Phe and [14C]Leu) were determined after 3 and 6 h of the GH infusion. Forearm deep vein GH rose to 35 +/- 6 ng/ml in response to GH, whereas systemic levels of GH, insulin, and insulin-like growth factor I (IGF-I) were unchanged. Forearm glucose uptake did not change during the study. After 6 h, GH suppressed forearm net release (3 vs. 6 h) of Phe (P less than 0.05), Leu (P less than 0.01), total branched-chain amino acids (P less than 0.025), and essential neutral amino acids (0.05 less than P less than 0.1). The effect on the net balance of Phe and Leu was due to an increase in the tissue uptake for Phe (71%, P less than 0.05) and Leu (37%, P less than 0.005) in the absence of any significant change in release of Phe or Leu from tissue. In the absence of any change in systemic GH, IGF-I, or insulin, these findings suggest that locally infused GH stimulates skeletal muscle protein synthesis. These findings have important physiological implications for both the role of daily GH pulses and the mechanisms through which GH can promote protein anabolism.

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

2006 ◽  
Vol 291 (3) ◽  
pp. E666-E674 ◽  
Author(s):  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Protein Synthesis ◽  
Free Fatty Acids ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Short Term ◽  
Lipid Infusion ◽  
Igf I ◽  
Plasma Ffas

Elevations in free fatty acids (FFAs) impair glucose uptake in skeletal muscle. However, there is no information pertaining to the effect of elevated circulating lipids on either basal protein synthesis or the anabolic effects of leucine and insulin-like growth factor I (IGF-I). In chronically catheterized conscious rats, the short-term elevation of plasma FFAs by the 5-h infusion of heparin plus Intralipid decreased muscle protein synthesis by ∼25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E·eIF4G complex to the inactive eIF4E·4E-BP1 complex. This shift was associated with a decreased phosphorylation of eIF4G but not 4E-BP1. Lipid infusion did not significantly alter either the total amount or phosphorylation state of mTOR, TSC2, S6K1, or the ribosomal protein S6 under basal conditions. In control rats, oral leucine increased muscle protein synthesis. This anabolic response was not impaired by lipid infusion, and no defects in signal transduction pathways regulating translation initiation were detected. In separate rats that received a bolus injection of IGF-I, lipid infusion attenuated the normal redistribution of eIF4E from the active to inactive complex and largely prevented the increased phosphorylation of 4E-BP1, eIF4G, S6K1, and S6. This IGF-I resistance was associated with enhanced Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1). These data indicate that the short-term elevation of plasma FFAs impairs basal protein synthesis in muscle by altering eIF4E availability, and this defect may be related to impaired phosphorylation of eIF4G, not 4E-BP1. Moreover, hyperlipidemia impairs IGF-I action but does not produce leucine resistance in skeletal muscle.

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